rs587778270

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000400.4(ERCC2):​c.1628A>T​(p.Gln543Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

ERCC2
NM_000400.4 missense

Scores

7
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.08
Variant links:
Genes affected
ERCC2 (HGNC:3434): (ERCC excision repair 2, TFIIH core complex helicase subunit) The nucleotide excision repair pathway is a mechanism to repair damage to DNA. The protein encoded by this gene is involved in transcription-coupled nucleotide excision repair and is an integral member of the basal transcription factor BTF2/TFIIH complex. The gene product has ATP-dependent DNA helicase activity and belongs to the RAD3/XPD subfamily of helicases. Defects in this gene can result in three different disorders, the cancer-prone syndrome xeroderma pigmentosum complementation group D, trichothiodystrophy, and Cockayne syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a region_of_interest Mediates interaction with MMS19 (size 199) in uniprot entity ERCC2_HUMAN there are 13 pathogenic changes around while only 2 benign (87%) in NM_000400.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.115629315).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ERCC2NM_000400.4 linkuse as main transcriptc.1628A>T p.Gln543Leu missense_variant 17/23 ENST00000391945.10 NP_000391.1 P18074-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ERCC2ENST00000391945.10 linkuse as main transcriptc.1628A>T p.Gln543Leu missense_variant 17/231 NM_000400.4 ENSP00000375809.4 P18074-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.054
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.040
CADD
Benign
20
DANN
Benign
0.88
DEOGEN2
Uncertain
0.44
T;T;T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.12
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-1.5
N;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
1.4
N;N;.
REVEL
Uncertain
0.35
Sift
Benign
1.0
T;T;.
Sift4G
Benign
1.0
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.47
MutPred
0.37
Loss of catalytic residue at Q543 (P = 0.074);.;.;
MVP
0.73
MPC
0.20
ClinPred
0.37
T
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.14
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587778270; hg19: chr19-45858025; API